Genetic alterations associated with progression from pancreatic intraepithelial neoplasia to invasive pancreatic tumor.
Genetic alterations associated with progression from pancreatic intraepithelial neoplasia to invasive pancreatic tumor.
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DOI：
10.1053/j.gastro.2013.07.049
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发表时间：
2013-11
期刊：
影响因子：
29.4
通讯作者：
Couch FJ
中科院分区：
文献类型：
--
作者：
Murphy SJ;Hart SN;Lima JF;Kipp BR;Klebig M;Winters JL;Szabo C;Zhang L;Eckloff BW;Petersen GM;Scherer SE;Gibbs RA;McWilliams RR;Vasmatzis G;Couch FJ
胰腺上皮内瘤变（PanIN）的分级增加与胰腺导管腺癌（PDAC）的进展相关。然而，控制从PanIN进展到PDAC的机制还不清楚。我们研究了这一过程中涉及的遗传改变。通过外显子组测序分析来自10名胰腺癌患者的激光捕获显微切割PDAC和邻近PanIN 2和PanIN 3病变的基因组DNA样本。在PanIN和肿瘤中发现了相似数量的体细胞突变，但突变负荷在病例之间差异很大。15个分离的PanIN中有10个与相关肿瘤共享超过50%的体细胞突变。肿瘤和克隆相关PanIN 2和PanIN 3病变常见的突变被鉴定为可促进致癌作用的基因。KRAS和TP53在PanIN和肿瘤中经常发生改变，但很少检测到其他反复修饰的基因。DNA损伤反应基因突变在所有样本中普遍存在。编码参与间隙连接、肌动蛋白细胞骨架、促分裂原活化蛋白激酶信号通路、轴突导向和细胞周期调控的蛋白质的基因是PanIN中最早的突变靶点，这些基因进展为PDAC。早期PanIN2病变似乎包含许多PDAC发展所需的体细胞基因改变。
Increasing grade of pancreatic intraepithelial neoplasia (PanIN) has been associated with progression to pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms that control progression from PanINs to PDAC are not well understood. We investigated the genetic alterations involved in this process. Genomic DNA samples from laser-capture microdissected PDACs and adjacent PanIN2 and PanIN3 lesions from 10 patients with pancreatic cancer were analyzed by exome sequencing. Similar numbers of somatic mutations were identified in PanINs and tumors, but the mutational load varied greatly among cases. Ten of the 15 isolated PanINs shared more than 50% of somatic mutations with associated tumors. Mutations common to tumors and clonally related PanIN2 and PanIN3 lesions were identified as genes that could promote carcinogenesis. KRAS and TP53 were frequently altered in PanINs and tumors, but few other recurrently modified genes were detected. Mutations in DNA damage response genes were prevalent in all samples. Genes that encode proteins involved in gap junctions, the actin cytoskeleton, the mitogen-activated protein kinase signaling pathway, axon guidance, and cell cycle regulation were among the earliest targets of mutagenesis in PanINs that progressed to PDAC. Early-stage PanIN2 lesions appear to contain many of the somatic gene alterations required for PDAC development.
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DOI：
10.1093/bioinformatics/btr612
发表时间：
2012-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Asmann YW;Middha S;Hossain A;Baheti S;Li Y;Chai HS;Sun Z;Duffy PH;Hadad AA;Nair A;Liu X;Zhang Y;Klee EW;Kalari KR;Kocher JP
通讯作者：
Kocher JP
DOI：
10.1073/pnas.94.17.9040
发表时间：
1997-08-19
影响因子：
11.1
作者：
Chang, KH;Chen, YM;Lee, WH
通讯作者：
Lee, WH
DOI：
10.1093/dnares/dss021
发表时间：
2012-10
期刊：
DNA research : an international journal for rapid publication of reports on genes and genomes
影响因子：
--
作者：
Murphy SJ;Cheville JC;Zarei S;Johnson SH;Sikkink RA;Kosari F;Feldman AL;Eckloff BW;Karnes RJ;Vasmatzis G
通讯作者：
Vasmatzis G
影响因子：
4.4
作者：
MORTON, CC;NUSSENZWEIG, MC;SHOWS, TB
通讯作者：
SHOWS, TB
影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.